Does Insulin Glargine Increase the Risk of Cancer

publicité
Epidemiology/Health Services Research
O R I G I N A L
A R T I C L E
Does Insulin Glargine Increase the
Risk of Cancer Compared With Other
Basal Insulins?
A French nationwide cohort study based on national administrative
databases
JEAN-PAUL FAGOT, PHARMD1
PIERRE-OLIVIER BLOTIÈRE, MSC1
PHILIPPE RICORDEAU, MD1
ALAIN WEILL, MD1
FRANÇOIS ALLA, MD, PHD2
HUBERT ALLEMAND, MD2
OBJECTIVEdTo explore in France the relationship between insulin glargine use and overall
and specific cancer risks in type 2 diabetic patients compared with other basal insulins.
RESEARCH DESIGN AND METHODSdData were extracted from French health insurance information system (Système National d’Information Inter-Régimes de l’Assurance Maladie) linked with data from the French Hospital Discharge database (Programme de
Médicalisation des Systèmes d’Information). Included were 70,027 patients aged 40–79 years
who started a basal insulin in 2007–2009. Cox proportional hazards models with age as timescale were used to calculate multivariate-adjusted hazard ratios for associations between type of
basal insulin and risk of overall cancer, breast cancer, and seven other cancer sites.
RESULTSdThe median follow-up was 2.67 years in patients exposed to insulin glargine.
Absolute event rates for all cancer in patients exposed to glargine versus other basal insulin users
were 1,622 and 1,643 per 100,000 person-years, respectively. No significant association was
observed between glargine exposure and overall cancer incidence after adjustment for sex, with a
hazard ratio of 0.97 (95% CI 0.87–1.07), or after additional adjustment for any other hypoglycemic agent use and duration of diabetes. No increased risk of breast cancer was observed for
glargine users compared with other basal insulins users, with a fully adjusted hazard ratio of 1.08
(0.72–1.62).
CONCLUSIONSdIn a large cohort of patients newly treated by basal insulin, no increased
risk of any cancer was observed in insulin glargine users compared with other basal insulin users.
Because follow-up did not exceed 4 years, longer-term studies are needed.
T
he publication in 2009 of four observational studies (1–4) raised the
question of a possible relationship
between the risk of developing tumors
and the type of insulin (i.e., human insulin and insulin analogs), particularly insulin glargine. Previous in vitro studies
comparing insulin glargine and human
insulin concluded that glargine had a
higher receptor affinity and mitogenic
potency (5). However, the in vivo
metabolism of insulin glargine in the
blood suggests a low mitogenic potency
due to the low affinity of its main metabolite for the IGF-1 receptor (6).
Overall, several differences concerning the methodology of published observational studies can be highlighted. In
particular, some studies compared insulin glargine and human insulin monotherapy only and excluded patients
exposed to both types of insulin in the
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
From the 1Strategy and Research Department, National Health Insurance, Paris, Ile de France, France; and the
2
General Division, National Health Insurance, Paris, Ile de France, France.
Corresponding author: Jean-Paul Fagot, [email protected]
Received 26 March 2012 and accepted 16 July 2012.
DOI: 10.2337/dc12-0506
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10
.2337/dc12-0506/-/DC1.
© 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
main or a secondary analysis (1,2) and/or
considered human insulin regardless of
the duration of activity compared with a
long-acting analog (1,2,4) and/or considered prevalent users (1–4), and one analysis included new users only (2). Several
adjustments for various variables, according to the data available in the databases used, also often led to conflicting
results within the same study. Moreover,
multiple subgroup analyses increased the
risk of spurious chance findings. The
German study (1) that found a significant
increased risk of total cancers for insulin
glargine was criticized (7,8); in particular,
Pocock and Smeeth (7) reported serious
errors in the methodology that made the
“article’s findings unsupportable.” They
also pointed out that the main results of
the first four cohort studies (1–4) and
clinical trials (9) did not show any significant increase in the overall incidence of
malignancy for insulin glargine compared with other insulins. However, the
cancer risk associated with insulin glargine remained an ongoing debate in late
2010, particularly in relation to breast
cancer.
We were therefore asked by the
French Medicines Agency (Agence française de sécurité sanitaire des produits de
santé [Afssaps]) in January 2011 to
conduct a study based on national administrative databases. The main objective of
this study was to estimate the relationship
between insulin glargine use and cancer
risk, especially breast cancer, in French
patients with type 2 diabetes compared
with other basal insulins.
RESEARCH DESIGN
AND METHODS
Study design and data source
We conducted an historical cohort study
based on data from the French National
Health Insurance information system (Système National d’Information Inter-Régimes
de l’Assurance Maladie [SNIIRAM]), which
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Diabetes Care Publish Ahead of Print, published online September 10, 2012
DIABETES CARE
1
Results of a type 2 diabetes cohort study
contains individualized, anonymous, and
comprehensive data on health spending reimbursements (10). The main demographic
data include age, sex, and vital status. Information on 100% reimbursed severe and
costly chronic diseases (affection de longue
durée [ALD] (11)) is available in the
SNIIRAM and coded according to the ICD10. These data can be linked to the French
Hospital Discharge database (Programme
de Médicalisation des Systèmes d’Information [PMSI]) (12). The PMSI database
provides detailed medical information on
all admissions in public and private hospitals, including discharge diagnoses
ICD-10 codes and medical procedures
performed during the hospital stay. The
linkage between SNIIRAM and PMSI databases has been previously used to conduct
several large epidemiological or postauthorization safety studies (13–15).
Data from SNIIRAM were only available from 2006. Specific approval was
obtained from the French data protection
agency (Commission nationale de l’informatique et des libertés [CNIL]) to perform this study during the planned
period.
Study population
For reasons of complete availability of
data during the whole study period, this
study was based on the national health
insurance general scheme, excluding students and civil servants, covering more
than 49 million people (i.e., 75% of the
French population).
The cohort contained new users of
long-acting or intermediate-acting insulin
during the years 2007, 2008, and 2009,
identified by the Anatomical Therapeutic
Chemical (ATC) code. Three groups were
defined according to first exposure to
insulin glargine (A10AE04), insulin detemir (A10AE05), or human intermediateacting or long-acting insulin (i.e., basal
human insulin [BHI]; A10AC01,
A10AD01, and A10AE01). Two distinct
prescriptions for the same type of basal
insulin were required within a 6-month
period to define exposure. To select a
population with type 2 diabetes, inclusion was limited to patients aged 40 to 79
years with at least three prescriptions for
any other hypoglycemic agent (OHA; i.e.,
ATC code A10B) in the calendar year
preceding insulin exposure. Patients were
defined as new users if they had no
prescription for any basal or bolus insulin
in 2006.
Excluded were patients with any discharge diagnosis of cancer (ICD-10 codes
2
DIABETES CARE
C00-C97, D00-D09, and D37-D48)
from 2005 to inclusion or within the
12 months after inclusion, or with cancer identified from ALD status since
1987.
Exposure
Exposure to insulin glargine or other
basal insulin was considered a timedependent variable. A patient was defined
as really exposed to a specific insulin after
12 months from the first reimbursement
until the end of follow-up, even after
treatment discontinuation. Moreover,
any switch to another type of basal insulin
was taken into account similarly. Exposure to any class of OHA was defined in a
similar way. The actual cumulative insulin dose from study entry to the last date
of prescription was considered to be a
time-dependent variable and calculated
by evenly distributing the total dose of
each basal insulin prescription over all of
the days between the date of the prescription and the date of the subsequent
prescription.
Outcomes
Outcomes analysis started from the 13th
month after the date of the first eligible
insulin reimbursement to the earliest of
the following events: occurrence of the
studied event (all cancer or specific cancer), loss to follow-up, defined by more
than 6 consecutive months without having filled any drug prescription, death
from any cause, or end of the observation
period on 31 December 2010. Patients
lost to follow-up were censored 2 months
after the start of the minimum 6-month
gap to allow enough time to observe any
incident cancer.
Cancer cases were identified by hospital discharge diagnoses (ICD-10 codes).
The two main outcomes were “all malignancies” (C00 to C97) and “breast cancer”
in women (C50). The incidence of cancers at seven other sites was also studied
for insulin glargine users: prostate (C61),
colorectal (C18 to C21), liver (C22), kidney (C64), bladder (C67), head and neck
(C00 to C14), and lung (C33 and C34)
cancers.
Confounding factors
The main potential confounders were age
at study entry, sex, use of any class of
OHA after inclusion, and information on
duration of diabetes, which was estimated
from the date of initiation of the ALD for
diabetes (when available). The following
classes of OHA were considered separately:
metformin, pioglitazone, rosiglitazone,
sulfonylureas, and other OHA. Together
with OHA comedication, screening tests
for breast and prostate cancer, hormone
replacement therapy (HRT), and hospitalizations for cardiovascular or cerebrovascular disease were identified during the
calendar year before inclusion. Women
aged 50 years or older were considered as
being treated with HRT (ATC codes
G03CA, G03FB, or G03HB) if they had
two or more annual prescriptions. Screening tests were collected by the corresponding codes in SNIIRAM for men aged 50
years or older (blood prostate-specific
antigen test) and women aged 50 to 74
years (mammography). Hospitalizations
for acute coronary syndrome and stroke
were identified from discharge diagnoses
(ICD-10 codes I21 to I23 and I60 to I64,
respectively).
Statistical analyses
Age, sex, OHA class use, and duration of
diabetes were compared using the x2 test
for categorical variables and the Wilcoxon
test for continuous variables. Other baseline characteristics (including admission
rates and screening tests) were compared
using the Mantel-Haenszel method with
adjustment for age and sex. Percentages
were age- and sex-standardized, including overall mortality rate during the first
year after study entry. Patients were classified into insulin glargine, insulin detemir, or BHI groups according to the first
insulin prescribed.
Crude incidence rates and incidence
rate ratios (IRR) of overall and sitespecific cancers were calculated with the
number of cancer cases and the corresponding exposure or nonexposure periods. Cox proportional hazards models
were used to calculate adjusted hazard
ratio (HR) estimates of cancer incidence
with insulin glargine, insulin detemir,
BHI, or OHA class and their 95% CI.
Age in calendar months was used as the
time scale. Several models with adjustment for potential confounders were performed: sex in model 1, sex and OHA
class use in model 2, and sex, OHA class
use, and duration of diabetes in model 3.
The same models were applied for cumulative doses classified into terciles. Other
potential confounders, such as screening
tests and HRT, were considered in model
2 for the main analysis only (i.e., insulin
glargine vs. other basal insulin users)
when the P value was # 0.2 for comparison of prevalences. Two sensitivity analyses were conducted: one used length of
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Fagot and Associates
follow-up in calendar months as the time
scale and age as covariate (10-year classes); another considered only a 6-month
period instead of a 12-month period for
the exclusion of cancers after inclusion
and for the defined time lag for exposure
to insulin glargine.
Associations were considered statistically significant for a P value ,0.05. Analyses were performed with SAS 9.1
software (SAS Institute, Cary, NC).
RESULTS
Description of the cohort population
From the 89,471 individuals potentially
eligible, 13,782 were excluded for cancer
before study entry or within the 12
months after study entry and 5,662 patients for follow-up of less than 12
months (see Supplementary Fig. 1). The
cohort included 70,027 patients; of these,
47,432 (67.7%) were treated with insulin
glargine only, 12,506 (17.9%) were treated with insulin detemir only, 4,564
(6.5%) were treated with BHI only, and
5,525 (7.9%) were treated successively
with at least two distinct long-acting or
intermediate-acting insulins. Among patients who initiated their insulin therapy
with insulin glargine, 5.4% subsequently
switched to another basal insulin. This
percentage was higher for insulin detemir
(12.9%) and BHI (18.5%). BHI actually
corresponded to intermediate-acting insulin only (i.e., neutral protamine Hagedorn
[NPH]) insulin, showing that long-acting
human insulin was already no longer prescribed in France and has totally been
replaced by analogs. Information on duration of diabetes was available for 58,889
patients (78.3%).
Patients exposed to insulin glargine
were slightly but significantly older than
those exposed to other basal insulins (P ,
0.0001; Table 1). The duration of diabetes
was comparable between the insulin glargine, insulin detemir, and BHI groups,
and did not differ significantly between
insulin glargine users and other basal insulins users. Patients exposed to insulin
glargine were more frequently exposed to
any OHA (87.2%) than patients exposed
to BHI (70.3%), but less frequently exposed than insulin detemir users (91.3%).
The all-cause mortality rate was
higher in BHI users (8.9%) than in insulin
glargine users (4.7%) and insulin detemir
users (3.5%; P , 0.0001). No significant
difference in hospitalizations for acute
coronary syndrome and stroke, or for
screening tests and HRT was observed
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between insulin glargine users and other
basal insulin users (Table 1).
Median follow-up was 2.67, 2.75,
and 2.83 years in patients exposed to
insulin glargine, insulin detemir, and
BHI, respectively. The median monthly
and cumulative doses were 722 and
21,000, 679 and 18,000, and 606 and
16,500 IU, respectively.
Association with cancer
A total of 1,391 malignancies of any type
were reported for patients exposed to
insulin glargine versus 405 in patients
exposed to insulin detemir and 191 in
BHI users. Crude incidence rates for
individuals exposed and not exposed to
insulin glargine were 1,622 and 1,643 per
100,000 person-years, respectively
(crude IRR 0.99 [95% CI 0.89–1.09];
Table 2). No significant association was
observed between insulin glargine exposure and incidence of any malignancy
after adjustment for sex (HR 0.97 [0.87–
1.07]) or after additional adjustment for
any OHA class use and duration of diabetes (Table 3). Comparable results were
observed in a similar analysis with insulin
detemir and BHI. A borderline significant
risk decrease was observed for metformin, with HR 0.87 (0.79–0.96) in model
2 and 0.87 (0.78–0.97) in model 3, and
sulfonylureas as well, with 0.89 (0.81–
0.97) and 0.86 (0.77–0.95). A stratified
analysisdnot initially planneddon metformin users versus nonusers led to comparable results in both groups for the
three models (Supplementary Table 1).
During follow-up, crude incidence rates
of breast cancer were 271 and 264 per
100,000 person-years for insulin glargine
versus nonusers, respectively (crude IRR
1.02 [0.71–1.47]; Table 3). No increased
risk of breast cancer was observed in any
model; in particular, the HR for glargine
was 1.01 (0.71–1.45) in model 1 and 1.08
(0.72–1.62) in model 3. Comparable results were observed for insulin detemir
and BHI (Table 3).
Similar results for insulin glargine
were observed when length of follow-up
was used as the time scale, with HR 0.97
(95% CI 0.88–1.08) for all cancers and
1.00 (0.70–1.44) for breast cancer (model
1; Supplementary Table 2). When
considering a 6-month period instead
of a 12-month period for the exclusion
of cancers after inclusion and for the defined time lag for exposure to insulin, the
results for insulin glargine remained nonsignificant for all cancers (0.95 [0.87–
1.04] in model 1) and breast cancer
(1.00 [0.72–1.37] in model 1; Supplementary Table 3).
Evaluation of a possible dose-effect
showed that no increased risk of cancer
was specifically observed in any model
for higher doses of insulin glargine
(27,000 IU and more), with HR in model
1 of 0.97 (0.84–1.11) for all malignancy
and 1.33 (0.85–2.09) for breast cancer in
women. Similar results were observed
for higher doses of insulin detemir or
BHI. However, a slight nonsignificant increase in point estimates was observed in
the three models for increased doses of
glargine and the occurrence of breast
cancer. No association was observed between insulin glargine use and the seven
other tumor sites compared with the use
of other basal insulins in any model
(Table 4).
CONCLUSIONSdInsulin glargine
was first marketed in France in mid2003. Using a large nationwide cohort
including more than 70,000 basal insulin
incident usersdto our knowledge the
largest study to date on this topicdwe
did not find any significant difference
in the risk of all cancers between new insulin glargine users and nonusers. We
also did not observe any difference in
breast cancer risk or the risk for seven
other malignancies between these two
groups. Interestingly, a significantly decreased risk was observed for metformin
and sulfonylureas users compared with
nonusers.
The two databases used are independent in data collection, resulting in a
decreased risk of selection biases. These
databases are considered to be comprehensive, because all French pharmacists
and all physicians in French hospitals
routinely contribute to data collection,
with annual quality control of coding.
This study presents several limitations. The maximum duration of followup was 4 years, and we therefore had no
information on the occurrence of cancers
after longer-term exposure. Besides, data
from French cancer registries established
in a few French areas (16) cannot be
linked to SNIIRAM and PMSI data. Consequently, stage of cancer and date of first
symptoms were not available in this
study. In some studies, however, regional
estimations of cancer incidence from the
PMSI database have been compared with
the incidence reported by local cancer
registries (17,18). One study reported a
good concordance between breast cancer
data from 12 departmental registries and
DIABETES CARE
3
4
DIABETES CARE
17,65 (25.2)
50.7
62.9 (10.2)
11.1
27.4
30.0
31.5
33.3
33.2
33.5
65.9
8.3
4.5
51.4
37.8
83.9
24.5
2.6
44.8
0.4
0.5
52,375 (74.8)
51.7
63.3 (10.1)
10.2
26.9
29.9
32.9
33.4
32.9
33.7
65.5
7.1
4.5
50.7
40.2
87.2
24.5
2.4
44.3
0.4
0.4
Nonexposed
Insulin glargine
0.67
0.61
0.96
0.42
0.39
0.28
,0.0001
0.66
0.09
,0.0001
,0.0001
0.5
0.4
25.1
2.9
45.8
71.8
9.9
5.3
57.5
45.3
91.3
32.9
33.9
33.2
62.3 (10.0)
11.5
29.6
30.3
28.6
,0.0001
,0.0001
0.80
16,639 (23.8)
50.2
Exposed
,0.0001
0.02
P
0.4
0.5
24.3
2.3
44.1
63.6
6.7
4.2
48.8
37.8
84.9
33.6
32.7
33.7
63.5 (10.1)
10.1
26.2
29.9
33.8
53,388 (76.2)
51.9
Nonexposed
Insulin detemir
0.47
0.48
0.6
0.6
23.5
1.9
41.6
53.7
5.7
2.9
41.0
29.3
70.3
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
0.23
0.004
0.01
33.7
31.3
35.0
64.1 (10.7)
11.5
22.4
27.6
38.6
6,666 (9.5)
49.1
Exposed
0.03
,0.0001
,0.0001
,0.0001
,0.0001
P
BHI
0.4
0.4
24.6
2.5
44.7
66.8
7.6
4.7
51.9
40.7
88.1
33.4
33.2
33.5
63.1 (10.0)
10.3
27.5
30.2
31.9
63,361 (90.5)
51.7
Nonexposed
0.06
0.01
0.30
0.05
0.001
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
0.01
,0.0001
,0.0001
,0.0001
,0.0001
P
0.4
0.4
24.5
2.4
44.4
65.6
7.4
4.5
50.9
39.6
86.4
33.4
33.0
33.6
63.2 (10.1)
10.4
27.0
30.0
32.6
70,027 (100.0)
51.5
Overall
population
Data are in percentages unless otherwise stated. Source SNIIRAM-PMSI, January 2006–December 2010. *Percentages were age- and sex-standardized. aWomen aged 50–74 years. bWomen $ 50 years. cMen $ 50 years.
N (%)
Men (%)
Age (years)
Mean (SD)
40–49
50–59
60–69
70–79
Duration of diabetes
(years) (N = 58,889)
,5
5–9
$10
Exposure to other antidiabetic
drugs during follow-up
Metformin
Pioglitazone
Rosiglitazone
Sulfonylureas
Other OHA
Total OHA
Cancer screening*
Mammographya
HRTb
PSA screeningc
Short-stay hospitalization
at baseline*
Acute coronary syndrome
Stroke
Exposed
Table 1dDemographic data and use of antidiabetic drugs during follow-up by long-acting or intermediate-acting insulin
Results of a type 2 diabetes cohort study
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Fagot and Associates
Table 2dCrude incidence rate ratios by long-acting or intermediate-acting insulin for all malignancies and breast cancer
Follow-up time (month)
All malignancies
Insulin glargine
Insulin detemir
BHI
Breast cancer (women)
Insulin glargine
Insulin detemir
BHI
Exposure
Patients (n)
Cases (n)
Total
Without exposure
Incidence ratea
IRR (95% CI)
E
NE
E
NE
E
NE
52,375
17,652
16,639
53,388
6,666
63,361
1,391
498
405
1,484
191
1,698
1,053,209
339,505
335,433
1,057,281
145,068
1,247,646
24,269
0
28,228
0
11,335
0
1,622
1,643
1,582
1,641
1,714
1,618
0.99 (0.89–1.09)
E
NE
E
NE
E
NE
25,298
8,687
8,302
25,683
3,401
30,584
114
40
38
116
15
139
518,051
168,985
169,470
517,566
75,659
611,377
12,502
0
15,802
0
5,907
0
271
264
297
261
258
270
1.02 (0.71–1.47)
0.96 (0.86–1.08)
1.06 (0.91–1.23)
1.14 (0.79–1.64)
0.96 (0.56–1.63)
Source SNIIRAM-PMSI, January 2006–December 2010. E, exposed; NE, nonexposed. aPer 100,000 person-years.
PMSI discharge diagnoses (17). Moreover, insulin users may differ in several
criteria according to insulin type, and
other adjustments, such as BMI, would
have been useful to improve this comparison. BMI and diabetes duration were
comparable among insulin users in two
U.K. studies (2,3), but BMI could not be
compared in French patients.
Another study limitation is the lack of
information on tobacco use, which is a
known risk factor for many cancers, particularly lung, head and neck, and bladder
cancers. This may also be an important
factor affecting the generalizability of our
results. However, further analysis concerning other cancer sites showed that there was
no difference between insulin glargine incident users and nonusers in the incidence
of lung cancer and head and neck cancer,
which supports the hypothesis that the
prevalence of smokers was comparable in
the two groups, as observed in the Scottish
study (2).
Our analysis only attributed a case of
cancer when this event occurred at least
12 months after start of exposure, a period that we considered to be possibly
relevant for inducing a cancer. However,
no consensus has been reached concerning the duration of cancer induction. We
therefore also considered a shorter period
of 6 months as a sensitive analysis, which
provided similar results. Furthermore, a
recent study (19) suggested that the
higher risks of cancer shortly after starting
insulin treatment might be explained by
protopathic bias. We also took into account any subsequent change in insulin
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exposure status and observed that only a
small proportion of patients in this cohort
(7.5%) were exposed to more than one
basal insulin. We also analyzed BHI users
versus nonusers and insulin detemir users
versus nonusers and found no difference
for cancer risks in these two analyses. In
addition, we only selected patients exposed
to long-acting or intermediate-acting insulin, as was done in a Taiwanese study (20),
because patients exposed to fast-acting insulin only might present several differences, such as severity of diabetes, level of
residual insulin, or comorbidities, compared with basal insulin users. We also
tried to improve group comparability by
not applying the monotherapy comparisons performed in some studies (1,21)
(i.e., users only exposed to the same basal
insulin during the study period), and conversely, we took into account all switches
from a basal insulin to another one. Moreover, we compared basal insulins with or
without short-acting insulin, and we did
not include individuals exposed to shortacting insulin only.
Because information on drug exposure was available only from 2006 onward, leading to a possible lack of data for
patients who initiated insulin therapy a
long time ago, we also selected new users
only rather than a fixed cohort. Moreover,
these patients were more likely to be
comparable in severity of diabetes or stage
of progression of the disease.
We considered that age was the most
appropriate time scale in the main Cox
regression model, because age is a known
risk factor for many cancers. For such
outcomes, the hazard is more likely to
be a function of age than time-on-study
(22). However an analysis was also performed with time-on-study as the time
scale and showed similar results, as in
the Taiwanese study (20).
Besides, the results of the multicenter
randomized Outcome Reduction With
Initial Glargine Intervention (ORIGIN)
trial have been recently published (23).
They were based on 12,537 people who
received insulin glargine or standard caredin an open-label designdand mainly
provided an analysis of cardiovascular
morbidity and/or mortality. The results
of the safety analysis on cancer were comparable with our study findings, as there
was no significant difference in the incidence of any cancer (HR 1.00 [95% CI
0.88–1.13]) with a median follow-up of
6.2 years.
No increased risk for breast cancer
was observed in our study, but a slight
nonsignificant trend was noted with increased doses of glargine. A recent in vitro
study showed that insulin glargine stimulated proliferation of breast adenocarcinoma cell line (MCF-7) compared with
regular human insulin (24). However, it is
unknown whether this finding supports
an increased risk of developing a breast
tumor in immunocompetent women. A
subgroup analysis in the first Swedish
study (4) showed a significantly increased
risk of breast cancer for glargine versus no
glargine use, but nonsignificant results
were observed for glargine and overall
cancer risk. A significant result was also
reported in the Scottish study (2) for the
DIABETES CARE
5
Results of a type 2 diabetes cohort study
Table 3dRisk of all malignancies and breast cancer, overall and with increasing level of insulin glargine, insulin detemir,
or BHI exposure during follow-up: adjusted HR estimated from the three multivariate Cox models with age as the time scale
All malignancies
Insulin glargine
Insulin detemir
BHI
Breast cancer (women)
Insulin glargine
Insulin detemir
BHI
Model 1a
Model 2b
Model 3c
Overall
[0–14,000 IU]
[14,000–27,000 IU]
27,000 IU and more
Overall
[0–14,000 IU]
[14,000–27,000 IU]
27,000 IU and more
Overall
[0–14,000 IU]
[14,000–27,000 IU]
27,000 IU and more
0.97 (0.87–1.07)
0.96 (0.85–1.08)
0.98 (0.86–1.11)
0.97 (0.84–1.11)
1.02 (0.91–1.13)
1.06 (0.91–1.23)
0.91 (0.75–1.10)
1.07 (0.87–1.31)
1.02 (0.88–1.19)
0.97 (0.78–1.21)
1.14 (0.88–1.48)
0.98 (0.73–1.32)
0.97 (0.88–1.08)
0.96 (0.85–1.08)
0.98 (0.86–1.11)
0.98 (0.85–1.12)
1.04 (0.93–1.16)
1.09 (0.93–1.26)
0.93 (0.76–1.12)
1.09 (0.89–1.33)
0.99 (0.85–1.15)
0.95 (0.77–1.18)
1.09 (0.84–1.41)
0.93 (0.69–1.25)
1.04 (0.93–1.16)
1.04 (0.91–1.18)
1.01 (0.88–1.16)
1.06 (0.91–1.24)
1.01 (0.89–1.13)
1.05 (0.88–1.23)
0.91 (0.73–1.12)
1.06 (0.85–1.32)
0.91 (0.76–1.08)
0.93 (0.73–1.18)
0.89 (0.65–1.21)
0.89 (0.63–1.24)
Overall
[0–14,000 IU]
[14,000–27,000 IU]
27,000 IU and more
Overall
[0–14,000 IU]
[14,000–27,000 IU]
27,000 IU and more
Overall
[0–14,000 IU]
[14,000–27,000 IU]
27,000 IU and more
1.01 (0.71–1.45)
0.91 (0.59–1.40)
0.91 (0.58–1.42)
1.33 (0.85–2.09)
1.16 (0.81–1.68)
1.28 (0.78–2.07)
0.99 (0.52–1.89)
1.18 (0.60–2.32)
0.93 (0.55–1.59)
1.05 (0.52–2.15)
1.27 (0.56–2.87)
0.27 (0.04–1.91)
1.00 (0.70–1.44)
0.90 (0.58–1.39)
0.91 (0.58–1.42)
1.31 (0.84–2.05)
1.10 (0.76–1.60)
1.20 (0.74–1.95)
0.95 (0.50–1.81)
1.12 (0.57–2.21)
1.02 (0.59–1.75)
1.11 (0.54–2.27)
1.41 (0.62–3.21)
0.30 (0.04–2.18)
1.08 (0.72–1.62)
0.88 (0.54–1.45)
1.02 (0.62–1.67)
1.49 (0.91–2.45)
1.08 (0.72–1.62)
1.13 (0.66–1.96)
1.02 (0.51–2.03)
1.04 (0.48–2.26)
1.03 (0.56–1.88)
1.21 (0.56–2.60)
1.51 (0.61–3.72)
0.00
Data are HR (95% CI) unless otherwise stated. Source SNIIRAM-PMSI, January 2006 - December 2010. aAdjusted for sex (all malignancies). bAdjusted for sex (all
malignancies) and OHA class use. cAdjusted for sex (all malignancies), OHA class use, and duration of diabetes.
prevalent users and for insulin glargine
monotherapy only. However, such a risk
was not found in three other analyses of
the Scottish study (2) or in the second
Swedish study published in early 2011
(25). The Swedish authors concluded
that the increased risk of breast cancer
observed in the 2006–2007 period in
Sweden and not in 2007–2008 was possibly due to chance. Four studies reported
more recent results (26–29). A moderate
increase was reported by Ruiter et al. (27)
for insulin glargine compared with human insulin, despite a significantly lower
risk of all malignancies for insulin glargine versus human insulin. This was not
observed for overall glargine in the three
other studies (26,28,29), but some subgroup analyses provided borderline significant results, including use over 5
Table 4dRisk of other cancer sites for glargine vs. other basal insulins: adjusted HR
estimated from the three multivariate Cox models with age as the time scale
Prostate
Colorectal
Liver
Kidney
Bladder
Lung
Head and neck
Model 1a
Model 2b
Model 3c
0.92 (0.65–1.30)
0.94 (0.70–1.25)
0.97 (0.69–1.37)
0.99 (0.51–1.92)
1.12 (0.74–1.70)
1.03 (0.76–1.41)
0.82 (0.46–1.44)
0.90 (0.64–1.28)
0.94 (0.71–1.26)
0.98 (0.69–1.38)
1.01 (0.52–1.94)
1.14 (0.75–1.72)
1.04 (0.76–1.42)
0.83 (0.47–1.46)
1.01 (0.68–1.48)
0.98 (0.72–1.32)
1.07 (0.72–1.59)
1.11 (0.54–2.26)
1.06 (0.67–1.66)
1.10 (0.78–1.57)
0.91 (0.48–1.72)
Data are HR (95% CI) unless otherwise stated. Source SNIIRAM-PMSI, January 2006–December 2010.
a
Adjusted for sex (except prostate). bAdjusted for sex (except prostate) and OHA class use. cAdjusted for sex
(except prostate), OHA class use, and duration of diabetes.
6
DIABETES CARE
years in a subgroup of women who had
been on insulin before starting glargine
(HR 2.7 [95% CI 1.1–6.5]) (26). However, there is no evidence of concordance,
as these significant results for the association of insulin glargine and breast cancer
were mainly observed in subgroups that
differed between studies. Moreover,
such a risk was not identified in the
ORIGIN trial (23) with a follow-up of up
to 7 years.
No significant difference was observed among incident users between
insulin glargine and other basal insulins
for the risk of prostate, colorectal, liver,
kidney, bladder, lung, and head and neck
cancers, in accordance with the great
majority of previously published findings, including recent results from the
General Practice Research Database
(GPRD) database (19). The Taiwanese
study recently reported a significant risk
increase for prostate cancer (20) for insulin glargine users versus nonusers.
Conversely, a significant protection for
colorectal cancer by insulin glargine was
reported in two recent studies (27,28).
care.diabetesjournals.org
Fagot and Associates
These findings were not identified in
other studies and could have resulted
from multiple comparisons or residual
confounding factors. At this time, the U.S.
Food and Drug Administration and the
European Medicines Agency have not
concluded that insulin glargine increases
the risk of any cancer, and the review of
this safety concern is still ongoing
(30,31).
This cohort study was conducted at
the request of the French Medicines
Agency (Afssaps) in response to a pharmacovigilance signal. No associations
were observed in incident users monitored up to 4 years between insulin
glargine and increased or decreased risk
of all malignancies, or for higher doses of
insulin glargine, compared with other
basal insulins. No risk increase was observed for breast cancer, specifically, or
for seven other tumor sites. This study,
based on data from large nationwide
administrative databases, therefore confirms the nonsignificant results of most
previous studies, although follow-up was
limited. Further studies with a longer
follow-up are needed to ensure continuous monitoring of cancer risk in patients
with diabetes mellitus.
3.
4.
5.
6.
7.
8.
9.
AcknowledgmentsdThe authors are employees of the French National Health Insurance and received no funding.
No potential conflicts of interest relevant to
this article were reported.
J.-P.F. was in charge of the literature search
and critical analysis, wrote the manuscript,
and contributed to defining the used methodology and to data interpretation. P.-O.B.
was in charge of data extraction from databases
and statistical analysis, contributed to defining
the used methodology and to data interpretation, and wrote the RESULTS report with
figures and tables. P.R., A.W., F.A., and H.A.
contributed to defining the used methodology
and to data interpretation. J.-P.F. is the guarantor of this work and, as such, had full access
to all the data in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
The authors thank Saskia Van Der Erf from
National Health Insurance for assistance in
writing the manuscript.
10.
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